Heparin Accelerates Gelsolin Amyloidogenesis
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- 作者：Ji Young Suk ; Fuming Zhang ; William E. Balch ; Robert J. Linhardt ; and Jeffery W. Kelly
- 刊名：Biochemistry
- 出版年：2006
- 出版时间：February 21, 2006
- 年：2006
- 卷：45
- 期：7
- 页码：2234 - 2242
- 全文大小：499K
- 年卷期：v.45,no.7(February 21, 2006)
- ISSN：1520-4995
文摘
The chemical environment of the extracellular matrix may influence the tissue-selectivedeposition observed there in gelsolin amyloid disease. Previously, we have identified the proteases thatgenerate the amyloidogenic fragments from the full-length gelsolin variants and demonstrated that heparinis capable of accelerating gelsolin amyloidogenesis. Herein, we identify the structural features of heparinthat promote the 8 kDa disease-associated gelsolin fragments (residues 173-243) generated at the cellsurface to form amyloid. In conjunction with electron microscopy analyses, our kinetic studies demonstratethat heparin efficiently accelerates the formation of gelsolin amyloid by enabling intermolecular 
-sheetformation. The use of heparin analogues reveals that sulfation is important in accelerating amyloidogenesisand that the extent of acceleration is proportional to the molecular weight of heparin. In addition, heparinaccelerated aggregation at both early and late stages of amyloidogenesis. Dynamic light scattering coupledto size exclusion chromatography showed that heparin promotes the formation of soluble aggregates.Collectively, these data reveal that heparin templates fibril formation and affords solubility to the aggregatingpeptides through its sulfated structure. By extension, the biochemical results herein suggest that tissue-selective deposition characteristic of the gelsolin amyloidoses is likely influenced by the extracellularlocalization of distinct glycosaminoglycans.
-sheetformation. The use of heparin analogues reveals that sulfation is important in accelerating amyloidogenesisand that the extent of acceleration is proportional to the molecular weight of heparin. In addition, heparinaccelerated aggregation at both early and late stages of amyloidogenesis. Dynamic light scattering coupledto size exclusion chromatography showed that heparin promotes the formation of soluble aggregates.Collectively, these data reveal that heparin templates fibril formation and affords solubility to the aggregatingpeptides through its sulfated structure. By extension, the biochemical results herein suggest that tissue-selective deposition characteristic of the gelsolin amyloidoses is likely influenced by the extracellularlocalization of distinct glycosaminoglycans.